Most organisms have evolved numerous regulatory mechanisms for sensing glucose and utilizing it efficiently. Glucose sensing and signaling in yeast remains an important paradigm for understanding molecular mechanisms that link extracellular signals to changes in an organism's transcriptional program. The budding yeast Saccharomyces cerevisiae has a distinctive fermentative life style?the preferential conversion of glucose into ethanol even under aerobic conditions?that it shares with many different tumor cells. This specialized glucose metabolism is accomplished by coordinated actions of two distinct glucose-regulated pathways: 1) the Rgt2/Snf3 glucose induction pathway that induces expression of glucose transporter genes (HXT);2) the Snf1-Mig1 glucose repression pathway that negatively regulates genes involved in respiration and the use of alternative sugars. The goal of the proposed research is to understand the role of glucose sensors in establishing not only the glucose induction but also the glucose repression of gene expression. In Aim 1, we will examine the mechanism by which glucose induction of HXT expression is achieved by the crosstalk between different glucose signaling pathways. In Aim 2, we will address the question of how the glucose sensors recognize and sense different levels of glucose. The glucose sensors are structurally similar to the glucose transporters but lack the ability to transport glucose. Achieving this aim would provide significant insights into the mechanism of glucose transport. Recent evidences suggest that Hxk2, one of the three hexose kinases, establishes an independent glucose repression pathway which is distinctive from the Snf1-Mig1 glucose repression pathway. The goal of aim 3 is to understand the Hxk2-mediated glucose signaling mechanism. In Aim 4, we will explore the multiple roles of the glucose sensors in glucose repression. We will specifically identify the regulatory role of the glucose sensors in inactivating the function of the Snf1 kinase, a yeast homolog of the AMP-activated protein kinase (AMPK), known to have direct links to diabetes and obesity. PUBLIC HEALTH RELEVANCE: The primary goal of the proposed research is to understand the complex crosstalk between the glucose signaling pathways in yeast. The proposed studies will provide significant insights into the processes involved in the maintenance of glucose homeostasis in humans, especially under pathological conditions, such as hyperglycemia in diabetics and the elevated rate of glycolysis observed in many solid tumors.